Abstract

Background

Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer
and is believed to contribute to tumor progression by silencing the expression of
tumor suppressor genes. Previously, we observed that promoter hypermethylation in
breast cancer reflects cell lineage rather than tumor progression and occurs at genes
that are already repressed in a lineage-specific manner. To investigate the generality
of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different
tissue types.

Results

We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer.
Nearly half of these genes varied in their susceptibility to hypermethylation between
different cancer types. We show that the expression status of hypermethylation prone
genes in the originator tissue determines their propensity to become hypermethylated
in cancer; specifically, genes that are normally repressed in a tissue are prone to
hypermethylation in cancers derived from that tissue. We also show that the promoter
regions of hypermethylation-prone genes are depleted of repetitive elements and that
DNA sequence around the same promoters is evolutionarily conserved. We propose that
these two characteristics reflect tissue-specific gene promoter architecture regulating
the expression of these hypermethylation prone genes in normal tissues.

Conclusions

As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue,
we suggest that their hypermethylation does not directly contribute to cancer development
via silencing. Instead aberrant hypermethylation reflects developmental history and
the perturbation of epigenetic mechanisms maintaining these repressed promoters in
a hypomethylated state in normal cells.